title: Low frequency of imprinting defects in ICSI children born small for gestational age.
abstract: Although there is an increased frequency of low birth weight after assisted reproduction, the mechanisms underlying this association are unclear. We have proposed that some of the children conceived by intracytoplasmic sperm injection (ICSI) with low birth weight might have an epimutation (faulty methylation pattern) in one of the imprinted genes involved in fetal growth control, eg, KCNQ1OT1, PEG1, PEG3, GTL2, IGF2/H19 and PLAGL1. Using bisulfite DNA sequencing and sequence-based quantitative methylation analysis (SeQMA), we determined the methylation pattern of these genes in buccal smears from 19 ICSI children born small for gestational age (SGA, birth weight <3rd percentile) and from 29 term-born normal weight children after spontaneous conception. We detected clear hypermethylation of KCNQ1OT1 and borderline hypermethylation of PEG1 in one and the same ICSI child. The other children and the parents of the affected child have normal methylation patterns. Imprinting defects appear to be a rare finding in ICSI children born SGA. Methylation of the paternal KCNQ1OT1 and PEG1 alleles may be a previously unrecognized cause of SGA. The epimutations found in the SGA child, whose father had oligozoospermia, probably result from an imprint erasure defect in the paternal germ line and therefore appear to be linked to the fertility problem of the father and not to in vitro fertilization/ICSI.
authors.affiliation: Institut für Humangenetik, Universitätsklinikum Essen, Essen, Germany.
authors.forename: Deniz
authors.initials: D
authors.lastname: Kanber
authors.forename: Karin
authors.initials: K
authors.lastname: Buiting
authors.forename: Michael
authors.initials: M
authors.lastname: Zeschnigk
authors.forename: Michael
authors.initials: M
authors.lastname: Ludwig
authors.forename: Bernhard
authors.initials: B
authors.lastname: Horsthemke
mesh_terms: D001483:Base Sequence; D018797:Cell Cycle Proteins / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D019175:DNA Methylation; D005260:Female; D018392:Genomic Imprinting; D006801:Humans; D007231:Infant, Newborn; D007236:Infant, Small for Gestational Age; D007335:Insulin-Like Growth Factor II / Q000235:genetics; D051741:Kruppel-Like Transcription Factors / Q000235:genetics; D016133:Polymerase Chain Reaction; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics; D011506:Proteins / Q000235:genetics; D062085:RNA, Long Noncoding; D017422:Sequence Analysis, DNA; D020554:Sperm Injections, Intracytoplasmic; D014157:Transcription Factors / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: D018797:Cell Cycle Proteins; C035170:IGF2 protein, human; C485621:KCNQ1OT1 long non-coding RNA, human; D051741:Kruppel-Like Transcription Factors; C498907:MEG3 non-coding RNA, human; C490820:PEG3 protein, human; C106464:PLAGL1 protein, human; D024642:Potassium Channels, Voltage-Gated; D011506:Proteins; D062085:RNA, Long Noncoding; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C103637:mesoderm specific transcript protein; D007335:Insulin-Like Growth Factor II